Cooke, Michael, Kubota, Yukihiko, Etheridge, Timothy, Szewczyk, Nathaniel, Higashitani, Atsushi, Sudevan, Surabhi, Takiura, Mai, Higashitani, Nahoko, Ellwood, Rebecca
[
International Worm Meeting,
2019]
Mitochondrial dysfunction impairs muscle health and causes subsequent muscle wasting. This study explores the role of mitochondrial dysfunction as an intramuscular signal for the extracellular matrix (ECM)-based proteolysis and consequentially, muscle cell dystrophy. We found that inhibition of mitochondrial electron transport chain causes paralysis as well as muscle structural damage in the nematode Caenorhabditis elegans. This was associated with a significant decline in collagen content. Both paralysis and muscle damage could be rescued with collagen IV overexpression, and calcium-dependent matrix metalloproteinase (MMP) and Furin inhibitors in Antimycin A treated animal as well as in the C. elegans Duchenne Muscular Dystrophy model. Additionally, muscle cytosolic calcium increased in the Antimycin A treated worms and its downregulation rescued the muscle damage. In our previous publication, we could see that heat stress leads to cytoplasmic calcium overload and mitochondrial fragmentation, and finally induced similar muscle structural damage (Momma K. et al 2017). These results suggest that calcium overload acts as one of the early triggers and activates Furin and MMPs for collagen degradation. In conclusion, we have established ECM degradation as an important pathway of muscle damage, and would like to propose MMP and Furin inhibitors as promising candidates for drugs against muscle wasting conditions characterized by mitochondrial dysfunction, including DMD but also heatstroke, ageing and disuse/ bedrest. Surabhi S. et al., Mitochondrial dysfunction causes Ca2+ overload and ECM degradation-mediated muscle damage in C. elegans. FASEB J 2019 in press. Monnma K. et al., Heat-Induced Calcium Leakage Causes Mitochondrial Damage in Caenorhabditis elegans Body-Wall Muscles. Genetics 2017, 206: 1985-1994.
[
International Worm Meeting,
2005]
As exposures to the space environment become longer, information regarding the effects on biological aging will become important. We have not yet fully clarified aging processes in space environments. The aging process and lifespan are affected by various kinds of environmental factors including oxygen concentration (1), temperature and radiation. The aging phenomena that we usually see occur under certain conditions on the ground. Space environments differ from ground environments especially with regard to the radiation spectrum and gravity. We participated in the International C. elegans Experiment(ICE)First that examined the effects of a 10-day space flight on the nematode C. elegans. C. elegans has frequently been used for study of aging because of its short lifespan. Recently, Morley et al. reported that Huntington's-like polyglutamine (polyQ)-repeat proteins expressed in the muscle of C. elegans form aggregates as the animals age, and that this aggregation is delayed in long-lived mutants(2). We measured the polyQ aggregates in these nematodes after space flight as an aging marker. Herndon et al. showed that the sarcomere orientation in the body-wall muscle becomes disorderly as the animals age(3). We also observed the sarcomere orientation in the body-wall muscle of these nematodes after space flight as another aging marker. Acknowledgement: We thank Dr. R. L. Morimoto (Northwestern University) for providing us polyQ-YFP C. elegans strains. We also thank CGC for other strains. ICE-First was mainly conducted by the French Space Agency (CNES), with support of the European Space Agency and the Space Research Organization of the Netherlands. We are grateful to Dr. Michel Viso (CNES), Dr. K. Kuriyama (JAXA) and Dr. A. Higashitani (Tohoku University) for their support and suggestion for our experiment. References: 1) Honda S., Ishii N, Suzuki K, Matsuo M. J Gerontol. 48:B57-61. 1993 2) James F. Morley, Heather R. Brignull, Jill J. Weyers, and Richard I. Morimoto. Proc. Natl. Acad. Sci. USA, 99: 10417-10422. 2002 3) Herndon LA, Schmeissner PJ, Dudaronek JM, Brown PA, Listner KM, Sakano Y, Paupard MC, Hall DH, Driscoll M. Nature. 419:808-814. 2002